Lung cancer is the most common cause of cancer death in the United States, accounting for more life lost than breast, prostate, colon and rectal cancer combined. Of the estimated 190,000 individuals who are diagnosed each year, over 180,000 succumb to the disease. Increasing insight into the molecular basis of lung cancer pathogenesis offers hope to combat this disease. Lung cancer development and progression involves the inactivation of tumor suppressor genes and activation of oncogenes. While the accumulation of genetic alterations has been shown to be involved in the progression of lung epithelial cells from hyperplasia, metaplasia, dysplasia, carcinoma in situ, invasive carcinoma, and finally metastatic carcinoma, recent work in the previous funding period of this SPORE project has demonstrated that epigenetic changes represent another important molecular change in lung cancer. With that background, the specific aims of the current proposal are: Specific aim 1. To utilize a newly derived microarray approach to identify novel hypermethylated genes which will help comprise methylation marker panels providing for full coverage of the non-small cell lung cancer genome. Specific aim 2. To utilize the marker panels from specific aim 1 to develop an epigenetic progression model based upon studies of precursor lesions and early stage lung cancer. Specific aim 3. To test the epigenetic marker panels for their efficacy as prognostic markers to identify patients with Stage I non-small cell lung cancer at very high risk for rapid disease recurrence.